Reduction of Tumor Blood Flow by Flavone Acetic Acid: A Possible Component of Therapy

Bibby, Michael C.; Double, J A; Loadman, Paul M.; Duke, C. V.

doi:10.1093/jnci/81.3.216

Cited by 104 publications

(40 citation statements)

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“…The low cytotoxicity of FAA against cell lines from FAA-responsive tumours (Finlay et al, 1988), suggests that its antitumour effect involves some interaction with host tissues. FAA affects both tumour structure and physiology, including haemorrhagic necrosis (Smith et al, 1987), a fall in ATP levels (Evelhoch et al, 1988), and a decrease in blood flow (Evelhoch et al, 1988;Bibby et al, 1989a). Recently we showed that this fall in tumour blood flow is progressive and irreversible, beginning within 15 minutes of FAA administration.…”

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confidence: 97%

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels

Zwi

Bc²,

Gavin³

et al. 1990

Br J Cancer

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Summary EMT6 multicellular spheroids were introduced into the peritoneal cavities of mice and allowed to become vascularised, resulting in solid spherical tumours. The necrotic cores of the initially avascular spheroids were replaced by vascularised tumour tissue but the outer zones of the spheroids failed to become vascularised. The presence of both vascular and avascular components in each spheroid allowed the role of the vasculature in the antitumour action of flavone acetic acid (FAA) to be determined. Eighteen hours after treatment with FAA 0.8 mmol kg-', the vascularised core became necrotic and haemorrhagic, while the outer avascular zone remained viable. Tumour Materials and methodsHistological studies EMT6 multicellular tumour spheroids were grown in spinner flask culture in a-MEM + 10% fetal calf serum, and between 15 and 25 spheroids, varying in size from 0.5 to 1.2 mm in diameter, were injected into the peritoneal cavities of anaesthetised Balb/C mice through a 161 gauge needle, as described previously (Zwi et al., 1989). Seven days later the mice in the treatment group (n = 7) were injected with FAA 0.8 mmol kg-' (kindly supplied by Dr K.D. Paull, National Cancer Institute) in 5% w/v sodium bicarbonate by the intravenous (i.v.) or intraperitoneal (i.p.) route, and were killed after a further 18 h. Untreated spheroid-bearing mice (n = 2) were killed after the same interval. The peritoneal cavities of the mice were opened, the free spheroids were collected, and those spheroids which had become attached to host structures were excised with a cuff of adjacent tissue. The spheroids were fixed in either 4% neutral formaldehyde or 2.5% phosphate buffered glutaraldehyde (pH 7.4). The formalin-fixed tissue was embedded in paraffin, and 5 gm sections were stained with haematoxylin and eosin (H&E). The glutaraldehyde-fixed spheroids were embedded in epoxy resin and 2 gim sections stained with toluidine blue. Multiple sections were examined from each spheroid.

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confidence: 97%

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels

Zwi

Bc²,

Gavin³

et al. 1990

Br J Cancer

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“…Podophyllotoxin was not applied clinically, however, because of its strong toxicity. A research group in the United Kingdom and New Zealand continued to develop this approach and found that drugs related to flavone acetic acid and tubulin-binding agents such as vinca alkaloids markedly decreased TBF (Bibby et al, 1989;Hill et al, 1989Hill et al, , 1993Zwi et al, 1989;Baguley et al, 1991;Ching et al, 1994;Chaplin et al, 1996;Holwell et al, 2001). However, the decrease in TBF by flavone acetic acid was accompanied by a marked reduction in systemic blood pressure, and an effective decrease in TBF by vinca alkaloids was achieved only at doses approaching the maximum tolerated dose.…”

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confidence: 99%

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

2002

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In a previous study, we used subcutaneous LY80 tumours (a subline of Yoshida sarcoma), Sato lung carcinoma, and methylcholanthrene-induced primary tumours, to demonstrate that a novel water-soluble combretastatin A-4 derivative, AC7700, abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour. In the present study, we investigated whether AC7700 acts in the same way against solid tumours growing in the liver, stomach, kidney, muscle, and lymph nodes. Tumour blood flow and the change in tumour blood flow induced by AC7700 were measured by the hydrogen clearance method. In a model of cancer chemotherapy against metastases, LY80 cells (2610 6 ) were injected into the lateral tail vein, and AC7700 at 10 mg kg 71 was injected i.v. five times at intervals of 2 days, starting on day 7 after tumour cell injection. The number and size of tumours were compared with those in the control group. The change in tumour blood flow and the therapeutic effect of AC7700 on microtumours were observed directly by using Sato lung carcinoma implanted in a rat transparent chamber. AC7700 caused a marked decrease in the tumour blood flow of all LY80 tumours developing in various tissues and organs and growth of all tumours including lymph node metastases and microtumours was inhibited. In every tumour, tumour blood flow began to decrease immediately after AC7700 administration and reached a minimum at approximately 30 min after injection. In many tumour capillaries, blood flow completely stopped within 3 min after AC7700 administration. These results demonstrate that AC7700 is effective for tumours growing in various tissues and organs and for metastases. We conclude that tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer.

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“…A number of studies has demonstrated that FAA has immunomodulatory activity (Ching & Baguley, 1987;Hornung et al, 1988; Ching & Baguley, 1988). Earlier studies in this laboratory have demonstrated that the establishment of a tumour vasculature may be necessary for the achievement of responses (Bibby et al, 1988b). More recent studies have shown that anti-tumour activity in subcutaneous tumours is accompanied by vascular shut-down and a reduction in tumour blood flow (Bibby et al, 1989a;Evelhoch et al, 1988;Zwi et al, 1989).…”

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confidence: 99%

“…Earlier studies in this laboratory have demonstrated that the establishment of a tumour vasculature may be necessary for the achievement of responses (Bibby et al, 1988b). More recent studies have shown that anti-tumour activity in subcutaneous tumours is accompanied by vascular shut-down and a reduction in tumour blood flow (Bibby et al, 1989a;Evelhoch et al, 1988;Zwi et al, 1989). Further investigations have shown that following FAA treatment in mice, clotting times were significantly reduced suggesting that possible intravascular coagulation occurs resulting in the vascular occlusion of tumours (Murray et al, 1989).…”

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confidence: 99%

Anti-tumour activity of flavone acetic acid (NSC 347512) in mice – influence of immune status

Bibby

Phillips²,

Double³

et al. 1991

Br J Cancer

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Summary Flavone acetic acid (FAA) is a synthetic flavonoid with dramatic pre-clinical anti-tumour activity involving a vascular component in its mechanism but no clinical effects have been seen to date. As FAA also has immunomodulatory activity, immunological factors might explain differences in activity between mouse and man. This study examines the influence of host immune status on the anti-tumour activity of FAA. Two human colon tumour xenografts (COBA, HT-29) fail to respond to FAA in nude mice. The lack of activity of FAA against HT-29 xenografts cannot be explained on the basis of limited drug bioavailability as achievable plasma, and tumour levels of FAA are similar to those seen in sensitive murine colon tumours. The immune status of the host also influences the activity of FAA against two transplantable tumours of the mouse colon. Both these tumours are highly responsive to FAA in their normal NMRI hosts, but neither tumours exhibited significant growth delay in thymectomised NMRI or nude hosts. Histological examination of treated tumours revealed significant areas of haemorrhagic necrosis in all three hosts. These data suggest a clear immunological component in the mechanism of action of FAA which is separate from the previously described haemorrhagic necrosis.

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Reduction of Tumor Blood Flow by Flavone Acetic Acid: A Possible Component of Therapy

Cited by 104 publications

References 0 publications

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

Anti-tumour activity of flavone acetic acid (NSC 347512) in mice – influence of immune status

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